Objective: To report the identification of a novel variant in the gene encoding alpha-synuclein (SNCA), segregating with Parkinson’s Disease (PD) in two families of Turkish origin.

Background: Missense variants and multiplications in SNCA are established as rare causes of PD. However, the mechanisms by which SNCA variants lead to neurodegeneration remain incompletely understood. The identification of additional PD-causing variants in this gene might shed light into the underlying mechanisms and the disease pathogenesis.

Method: Sanger sequencing of the entire SNCA coding region was performed in the index case of the first family, while the index patient of the second family underwent testing by whole exome sequencing. Co-segregation analysis was performed in the two families and subsequently, haplotype analysis across the SNCA locus was carried out. Functional studies included in vitro thioflavin-T aggregation assay and in silico structural modelling of the alpha-synuclein (α-syn) protein.

Results: We identified a novel SNCA variant, c.215C>T (p.Thr72Met), segregating with PD in a total of four members in the two families. Evidence of a shared haplotype across the SNCA locus was found among variant carriers, suggestive of a common founder. We next showed that the Thr72Met α-syn displays enhanced aggregation in-vitro, compared to the wild-type species. Mapping the location of Thr72 on the tetrameric α-syn model of Wang et al. [1] revealed that Thr72 lies in the tetrameric interface, and substitution with the much larger methionine residue could potentially lead to destabilization of the tetramer.

Conclusion: We present clinical, genetic, and functional data that support a causative role of the SNCA c.215C>T (p.Thr72Met) variant in familial PD. Testing for this variant in patients with familial or sporadic PD, especially of Turkish origin, might detect additional carriers. Further functional analyses might offer new insights into the shared biochemical properties of the p.Thr72Met and the other PD-causing SNCA missense variants, and how they lead to neurodegeneration.

References: [1] Wang W, Perovic I, Chittuluru J, et al. A soluble α-synuclein construct forms a dynamic tetramer. Proc Natl Acad Sci U S A. 2011;108(43):17797-17802. doi:10.1073/pnas.1113260108

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-new-alpha-synuclein-missense-variant-thr72met-in-two-turkish-families-with-parkinsons-disease/